PARP7 Inhibitors and AHR Agonists Act Synergistically Across a Wide-Range of Cancer Models.

Small molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated as a monotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by co-treatment with agonists of the Aryl Hydrocarbon Receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. Here we demonstrate that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to the combination. Our data show that this synergistic response is dependent on AHR/ARNT and is associated with increased levels of nuclear AHR and increased transcription of AHR target genes. In some hormone receptor-positive cell lines, we find that combination treatment is associated with proteasomal turnover of the steroid hormone receptors, androgen receptor and estrogen receptor. Both wildtype and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy.

Male Survivors of Institutional Child Sexual Abuse: A Review.

Male child sexual abuse is over-represented in institutional settings. This realization has increasingly come into public focus in recent decades initially through lived experience, often with male survivors' stories told in the media and subsequently through court cases and government inquiries. Beginning at the turn of the century with the Irish Commission to Inquire into Child Abuse (1999-2009), numerous national and state inquiries into institutional child abuse followed around the world. This scoping review asks the question: What is known from the research about the institutional child sexual abuse of males? Conducted in 2023 five databases were used (APA PsycINFO, CINAL, Medline, Scopus, Web of Science) producing 973 studies for screening. Applying the Arksey and O'Malley framework resulted in 29 studies meeting the inclusion criteria, which were analyzed. Of the 29 studies, 27 could be categorized into 3 broad areas of focus: survivor experience, impact, and disclosure. Two further studies considered: turning points and meaning making. The findings are discussed under the following headings: disclosure, impacts (emotional, mental health, alcohol, and other impacts), and what is helpful to victim/survivors. Implications for practice, policy, and research are examined along with limitations of the current research.

The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2.

SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation of Mac1 abrogates viral replication in vivo by potentiating host innate immune responses. However, it is unknown whether this can be achieved by pharmacologic inhibition and can therefore be exploited therapeutically. Here we report a potent and selective lead small molecule, AVI-4206, that is effective in an in vivo model of SARS-CoV-2 infection. Cellular models indicate that AVI-4206 has high target engagement and can weakly inhibit viral replication in a gamma interferon- and Mac1 catalytic activity-dependent manner; a stronger antiviral effect for AVI-4206 is observed in human airway organoids. In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral replication, potentiates innate immune responses, and leads to a survival benefit. Our results provide pharmacological proof of concept that Mac1 is a valid therapeutic target via a novel immune-restoring mechanism that could potentially synergize with existing therapies targeting distinct, essential aspects of the coronaviral life cycle. This approach could be more widely used to target other viral macrodomains to develop antiviral therapeutics beyond COVID-19.

Promoting men-inclusive maternity services: exploring the expectations, experiences and needs of men as fathers.

AIM: This study aimed to explore the 'real time' expectations, experiences and needs of men who attend maternity services to inform the development of strategies to enhance men's inclusion. METHODS: A qualitative descriptive design was adopted for the study. Semi-structured face-to-face or telephone interviews were conducted with 48 men attending the Royal Brisbane and Women's Hospital before and after their partner gave birth. Data were coded and analysed thematically. RESULTS: Most respondents identified their role as a support person rather than a direct beneficiary of maternity services. They expressed the view that if their partner and baby's needs were met, their needs were met. Factors that contributed to a positive experience included the responsiveness of staff and meeting information needs. Factors promoting feelings of inclusion were being directly addressed by staff, having the opportunity to ask questions, and performing practical tasks associated with the birth. CONCLUSION: Adopting an inclusive communication style promotes men's feelings of inclusion in maternity services. However, the participants' tendency to conflate their needs with those of their partner suggests the ongoing salience of traditional gender role beliefs, which view childbirth primarily as the domain of women.

Biomechanical Motion Changes in Adjacent and Noncontiguous Segments Following Single-Level Anterior Cervical Discectomy and Fusion: A Computed Tomography-Based 3D Motion Capture Study.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is known to elicit adverse biomechanical effects on immediately adjacent segments; however, its impact on the kinematics of the remaining nonadjacent cervical levels has not been understood. This study aimed to explore the biomechanical impact of ACDF on kinematics beyond the immediate fusion site. We hypothesized that compensatory motion following single-level ACDF is not predictably distributed to adjacent segments due to compensation from noncontiguous levels. METHODS: Six fresh-frozen cervical spines (C2-T1) underwent fluoroscopic screening and sagittal and coronal reformats from computed tomography scans and were utilized to grade segmental degeneration. Each specimen was tested to 30° of flexion and extension intact and following single-level ACDF at the C5-C6 level. The motions of each vertebral body were tracked using 3-dimensional (3D) motion capture into an inverse kinematics model, facilitating correlations between the 3D reconstruction from computed tomography images and the 3D motion capture data. This model was used to calculate each level's flexion/extension range of motion (ROM). RESULTS: Single-level fusion at the C5-C6 level across all specimens resulted in a significant motion reduction of -6.8° (P = 0.002). No significant change in ROM occurred in the immediate adjacent segments C4-C5 (P = 0.07) or C6-C7 (P = 0.15). Hypermobility was observed in 2 specimens (33%) exclusively in adjacent segments. In contrast, the other 4 spines (66%) displayed hypermobility at noncontiguous segments. Hypermobility occurred in 42% (5/12) of the adjacent segments, 28% (5/18) of the noncontiguous segments, and 50% (3/6) of the cervicothoracic segments. CONCLUSION: Single-level ACDF impacts ROM beyond adjacent segments, extending to noncontiguous levels. Compensatory motion, not limited to adjacent levels, may be influenced by degenerative changes in noncontiguous segments. Surprisingly, hypermobility may not occur in adjacent segments after ACDF. CLINICAL RELEVANCE: Overall, the multifaceted biomechanical effects of ACDF underscore the need for a comprehensive understanding of cervical spine dynamics beyond immediate adjacency, and it needs to be taken into consideration when planning single-level ACDF.

Intersections of Intimate Partner Violence and Natural Disasters: A Systematic Review of the Quantitative Evidence.

Natural disasters and extreme weather events are increasing in both intensity and frequency. Emerging evidence suggests that there is a relationship between intimate partner violence (IPV) and natural disasters. However, there is a scarcity of methodologically sound research in this area with no systematic review to date. To address the gap, this paper systematically assesses the quantitative evidence on the association between IPV with natural disasters between 1990 and March 2023. There were 27 articles that meet the inclusion criteria for the data extraction process. A quantitative critical appraisal tool was used to assess the quality of each study and a narrative synthesis approach to explore the findings. The review found an association between IPV and disasters, across disaster types and countries. However, more research is needed to explore the nuances and gaps within the existing knowledge base. It was unclear whether this relationship was causal or if natural disasters heightened existing risk factors. Further, it is inconclusive as to whether disasters create new cases of IPV or exacerbate existing violence. The majority of studies focused on hurricanes and earthquakes with a dearth of research on "slow onset disasters." These gaps represent the need for further research. Further research can provide a more thorough understanding of IPV and natural disasters, increasing stakeholders' ability to strengthen community capacity and reduce IPV when natural disasters occur.

Large tandem duplications in cancer result from transcription and DNA replication collisions.

Despite the abundance of somatic structural variations (SVs) in cancer, the underlying molecular mechanisms of their formation remain unclear. Here, we use 6,193 whole-genome sequenced tumors to study the contributions of transcription and DNA replication collisions to genome instability. After deconvoluting robust SV signatures in three independent pan-cancer cohorts, we detect transcription-dependent replicated-strand bias, the expected footprint of transcription-replication collision (TRC), in large tandem duplications (TDs). Large TDs are abundant in female-enriched, upper gastrointestinal tract and prostate cancers. They are associated with poor patient survival and mutations in TP53, CDK12, and SPOP. Upon inactivating CDK12, cells display significantly more TRCs, R-loops, and large TDs. Inhibition of G2/M checkpoint proteins, such as WEE1, CHK1, and ATR, selectively inhibits the growth of cells deficient in CDK12. Our data suggest that large TDs in cancer form due to TRCs, and their presence can be used as a biomarker for prognosis and treatment.

Novel approach to prenatal predictors of outcomes for fetuses with severe Ebstein anomaly.

OBJECTIVE: Ebstein anomaly (EA) is a cardiac malformation with highly variable presentation and severity with limited perinatal management options. We present incorporation of fetal lung measurements into a multidisciplinary evaluation for counseling and predicting postnatal outcomes in patients with severe EA. METHODS: Five fetuses with severe fetal EA were reviewed. Third trimester sonographic observed/expected total lung area (O/E TLA) and lung to head ratio (O/E LHR), fetal MRI total fetal lung volume ratio (O/E-TFLV), echocardiographic cardio-thoracic ratio (CT ratio), sonographic estimated fetal weight (EFW) by Hadlock formula and presence of hydrops, were used to guide perinatal management. RESULTS: Three of five had appropriate fetal growth, were delivered at term in a cardiac operative suite, and underwent immediate intervention with good neonatal outcomes. Two had severe fetal growth restriction (FGR), CT ratios > 0.8 and O/E LHR and TLA < 25%. One of which delivered prematurely with neonatal demise and one suffered in utero demise at 34 weeks. CONCLUSIONS: FGR, hydrops, increased CT ratio and reduced O/E LHR and TFLV are potential prognosticators of poor outcomes in severe EA, and should be validated in larger cohorts that would allow for a statistical analysis of the predictive utility of these measurements.

Pulmonary hypoplasia is associated with severe morbidityThere are limited prognosticating tools to risk stratify and guide management in cases of severe prenatal Ebstein anomaliesFetal MRI may improve prognostication for fetuses with EA.

A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication in vivo.

Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the role of Mac1 catalytic activity in viral replication, we generated recombinant viruses and replicons encoding a catalytically inactive NSP3 Mac1 domain by mutating a critical asparagine in the active site. While substitution to alanine (N40A) reduced catalytic activity by ~10-fold, mutations to aspartic acid (N40D) reduced activity by ~100-fold relative to wild-type. Importantly, the N40A mutation rendered Mac1 unstable in vitro and lowered expression levels in bacterial and mammalian cells. When incorporated into SARS-CoV-2 molecular clones, the N40D mutant only modestly affected viral fitness in immortalized cell lines, but reduced viral replication in human airway organoids by 10-fold. In mice, the N40D mutant replicated at >1000-fold lower levels compared to the wild-type virus while inducing a robust interferon response; all animals infected with the mutant virus survived infection. Our data validate the critical role of SARS-CoV-2 NSP3 Mac1 catalytic activity in viral replication and as a promising therapeutic target to develop antivirals.

A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication and pathogenesis in vivo.

Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the therapeutic potential of Mac1 inhibition, we generated recombinant viruses and replicons encoding a catalytically inactive NSP3 Mac1 domain by mutating a critical asparagine in the active site. While substitution to alanine (N40A) reduced catalytic activity by ~10-fold, mutations to aspartic acid (N40D) reduced activity by ~100-fold relative to wildtype. Importantly, the N40A mutation rendered Mac1 unstable in vitro and lowered expression levels in bacterial and mammalian cells. When incorporated into SARS-CoV-2 molecular clones, the N40D mutant only modestly affected viral fitness in immortalized cell lines, but reduced viral replication in human airway organoids by 10-fold. In mice, N40D replicated at >1000-fold lower levels compared to the wildtype virus while inducing a robust interferon response; all animals infected with the mutant virus survived infection and showed no signs of lung pathology. Our data validate the SARS-CoV-2 NSP3 Mac1 domain as a critical viral pathogenesis factor and a promising target to develop antivirals.

Optimizing Referral Timing of Patients With Fontan Circulatory Failure for Heart Transplant.

BACKGROUND: There are no criteria guiding the timing of heart transplant referral for Fontan patients, nor are there any characteristics of those deferred or declined listing reported. This study examines comprehensive transplant evaluations for Fontan patients of all ages, listing decisions, and outcomes to inform referral practices. METHODS: Retrospective review of 63 Fontan patients formally assessed by the advanced heart failure service and presented at Mayo Clinic transplant selection committee meetings (TSM) January 2006 to April 2021. The study is compliant with the Helsinki Congress and Declaration of Istanbul and included no prisoners. Statistical analysis was performed with Wilcoxon Rank Sum and Fisher's Exact tests. RESULTS: Median age at TSM was 26 years (17.5, 36.5). Most were approved (38/63 [60%]); 9 of 63 (14%) were deferred and 16 of 63 (25%) were declined. Approved patients more commonly were <18 years old at TSM (15/38 [40%] vs 1/25 [4%], P = .002) compared with those deferred/declined. Complications of Fontan circulatory failure were less common in approved vs deferred/declined patients: ascites (15/38 [40%] vs 17/25 [68%], P = .039), cirrhosis (16/38 [42%] vs 19/25 [76%], P = .01), and renal insufficiency (6/38 [16%] vs 11/25 [44%], P = .02). Ejection fraction and atrioventricular valve regurgitation did not differ between groups. Pulmonary artery wedge pressure was overall high normal (12 mm Hg [9,16]) but higher in deferred/declined vs approved patients, 14.5 (11, 19) vs 10 (8, 13.5) mm Hg, P = .015. Overall survival was significantly lower in deferred/declined patients (P = .0018). CONCLUSION: Fontan patient referral for heart transplant at younger age and before the onset of end-organ complications is associated with increased approval for transplant listing.

Myocardial Work in Echocardiography.

Myocardial work is an emerging tool in echocardiography that incorporates left ventricular afterload into global longitudinal strain analysis. Myocardial work correlates with myocardial oxygen consumption, and work efficiency can also be assessed. Myocardial work has been evaluated in a variety of clinical conditions to assess the added value of myocardial work compared to left ventricular ejection fraction and global longitudinal strain. This review showcases the current use of myocardial work in adult echocardiography and its possible role in cardiac pathologies.

How Does Cross-Sectional Imaging Impact the Management of Patients With Single Ventricle After Bidirectional Cavopulmonary Connection?

BACKGROUND: There is currently no consensus regarding the use of surveillance cross-sectional imaging in pediatric patients after bidirectional cavopulmonary connection (BDCPC). We sought to determine how computed tomography with angiography (CTA) and cardiac magnetic resonance (CMR) imaging impacted the clinical management of pediatric patients after BDCPC. METHODS: A single-center retrospective study including patients with single ventricle who had BDCPC between 2010 and 2019, and CTA/CMR studies obtained in these patients, at ≤5 years of age, and with Glenn physiology. Repeat studies on the same patient were included if the clinical situation had changed. The impact of CTA/CMR studies was categorized as major, minor, or none. RESULTS: Twenty-four patients (63% male) and 30 imaging studies (22 CTAs) were included. 60% were obtained in patients with hypoplastic left heart syndrome (HLHS); most common indication was Follow-up after an intervention (23%). 6 CMRs were performed on stable HLHS patients as part of a research protocol, with no clinical concerns. The overall impact of CTA/CMR studies was major in 13 cases (43.3%). CTA/CMR studies performed ≥1 year of age (62.5% vs 21.4%, P = .02) and in non-HLHS patients (66.7% vs 27.8%, P = .035) were associated with major impact. Also, 2/6 Research studies were associated with a major impact. CONCLUSIONS: CTA/CMR imaging in pediatric patients with SV after BDCPC was associated with significant clinical impact in over 40% of cases, with a higher impact if obtained in patients ≥1 year of age and in non-HLHS patients. We cannot disregard the possibility of CMR as a surveillance imaging modality in this population.

Technology-Facilitated Abuse Against Women From Culturally and Linguistically Diverse Backgrounds: A Scoping Review of the Literature.

Women from culturally and linguistically diverse (CALD) backgrounds are particularly vulnerable to domestic and family violence, including technology-facilitated abuse. Often CALD women depend on technology to connect with support networks in their home country. Technology-facilitated abuse can be devastating and isolating. There is limited comprehensive knowledge of how technology-facilitated abuse is experienced by CALD women. This scoping review addresses this gap by exploring and analysing the available literature on technology-facilitated abuse amongst CALD women in the context of domestic and family violence. Employing a scoping review methodology, a total of nine studies were identified from a database search and other sources (including snowball, web search, and search verification processes). Studies were included if they contained the following three elements: (1) a focus on technology-facilitated abuse, (2) the inclusion of CALD women's experiences, and (3) a context of domestic and family violence (DFV). This review firstly maps the methodologies and characteristics of the studies. Second, the most common types of technology-facilitated abuse that disproportionally affect CALD women are identified together with culturally related help-seeking barriers. Areas for future research are discussed along with suggestions for improving practises and policies for prevention and intervention.

The Impact of Critical Life Points and Events for Survivors of Institutional Child Sexual Abuse: Understanding Trauma and the Role of Compensation in Recovery.

Although the impact of child sexual abuse (CSA) is well documented in the international literature, little is known about the critical points of recovery across the life course for survivors of institutional CSA. The aim of this study was to identify critical points, or events across the life course that may increase, or decrease, a survivor's vulnerability to the complex traumatization of institutional CSA (ICSA). The sample consisted of two hundred and forty-eight witness statements extracted from the 56 publicly available case studies presented to the Australian Royal Commission into Institutional Responses to Child Sexual Abuse during 2013-2016 (Commonwealth of Australia, 2017). A content analysis and thematic coding of the statements identified seven main themes in the witness statements (Gender, Organization, Triggers, Trauma, Mental Health, Intervention and Compensation), that appeared to be critical events across the life course. The themes were transformed into variables for further analysis using SPSS. Significant Likelihood Ratios were found between associations with the organization where the abuse occurred and between triggers and breastfeeding/sensory, breast feeding/childcare, emotional and physical distress, and mental health (p < 0.01). Significant associations were also found between receiving compensation for the CSA and triggers, trauma, breast feeding-sensory and childcare (p < 0.05) and gender and breast feeding (p < 0.05). Overall, the findings showed that triggers can be random across the life course occurring mainly through indirect association, or in situations that evoke memories of the CSA, and that receiving compensation can assist survivors in their recovery journey. The findings also indicate the need for health care professionals to be aware of the critical points in a CSA survivor's recovery and how triggers may impact on their mental welling throughout the life course.

Bearing Witness as a Process for Responding to Trauma Survivors: A Review.

Bearing witness is a means for trauma survivors to give voice to lived experience. Bearing witness has been used in national and international commissions, inquiries, and tribunals to hear directly from survivors of abuse and trauma. This scoping review examines the documented research on the experience of survivors of trauma bearing witness. In 2021, six electronic data bases were searched-EBSCO, Informit, CINHAL, Clarivate, ProQuest, and Sage-and a search of the gray literature, revealed 1,201 references for studies between 1990 and 2021. After applying the Arksey and O'Malley framework, 21 studies that met inclusion criteria were identified. The inclusion criteria focused on studies where survivors expressed their views on bearing witness to trauma in official processes inclusive of public or private testimony, verbal or written. These studies utilized a range of methodologies and designs that represented the perspectives of 3,192 survivors of trauma who had borne witness. Analysis of the studies resulted in key findings under four themes: healing versus re-traumatization, support and safety of survivors, engaging and involving survivors, and culture and context. The literature indicates that bearing witness is a critical means to give voice to survivors of trauma and to provide them with acknowledgment; however, the literature is inconclusive regarding the impact of bearing witness on survivors. More research is required to better understand how survivors can best benefit and be supported by processes of bearing witness, and not be harmed or re-traumatized.

Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2.

Over one million cases of gastric cancer are diagnosed each year globally, and the metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors of ATR, a key regulator of the DNA damage response, are now in clinical development as targeted agents for gastric cancer. Here, we performed a large-scale CRISPR interference screen to discover genetic determinants of response and resistance to ATR inhibitors (ATRi) in gastric cancer cells. Among the top hits identified as mediators of ATRi response were UPF2 and other components of the nonsense-mediated decay (NMD) pathway. Loss of UPF2 caused ATRi resistance across multiple gastric cancer cell lines. Global proteomic, phosphoproteomic, and transcriptional profiling experiments revealed that cell-cycle progression and DNA damage responses were altered in UPF2-mutant cells. Further studies demonstrated that UPF2-depleted cells failed to accumulate in G1 following treatment with ATRi. UPF2 loss also reduced transcription-replication collisions, which has previously been associated with ATRi response, thereby suggesting a possible mechanism of resistance. Our results uncover a novel role for NMD factors in modulating response to ATRi in gastric cancer, highlighting a previously unknown mechanism of resistance that may inform the clinical use of these drugs. SIGNIFICANCE: Loss of NMD proteins promotes resistance to ATR inhibitors in gastric cancer cells, which may provide a combination of therapeutic targets and biomarkers to improve the clinical utility of these drugs.

RASA2 ablation in T cells boosts antigen sensitivity and long-term function.

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.

A Whole-Genome CRISPR Screen Identifies AHR Loss as a Mechanism of Resistance to a PARP7 Inhibitor.

Inhibitors directed toward PARP1 and PARP2 are approved agents for the treatment of BRCA1 and BRCA2-related cancers. Other members of the PARP family have also been implicated in cancer and are being assessed as therapeutic targets in cancer and other diseases. Recently, an inhibitor of PARP7 (RBN-2397) has reached early-stage human clinical trials. Here, we performed a genome-wide CRISPR screen for genes that modify the response of cells to RBN-2397. We identify the polycyclic aromatic hydrocarbon receptor AHR and multiple components of the cohesin complex as determinants of resistance to this agent. Activators and inhibitors of AHR modulate the cellular response to PARP7 inhibition, suggesting potential combination therapy approaches.

From Safety to Benefit in Cell Delivery During Surgical Repair of Ebstein Anomaly: Initial Results.

BACKGROUND: The objective of this study is to assess the safety and early impact of intramyocardial delivery of autologous bone marrow-derived mononuclear cells (BM-MNC) at time of surgical Ebstein repair. METHODS: Patients with Ebstein anomaly (ages 6 months to 30 years) scheduled to undergo repair of the tricuspid valve were eligible to participate in this open-label, non-randomized phase I clinical trial. BM-MNC target dose was 1-3 million cells/kg. Ten patients have undergone surgical intervention and cell delivery to the right ventricle (RV) and completed 6-month follow-up. RESULTS: All patients underwent surgical tricuspid valve repair and uneventful BM-MNC delivery; there were no ventricular arrhythmias and no adverse events related to study product or delivery. Echocardiographic RV myocardial performance index improved and RV fractional area change showed an initial decline and then through study follow-up. There was no evidence of delayed myocardial enhancement or regional wall motion abnormalities at injection sites on 6-month follow-up magnetic resonance imaging. CONCLUSIONS: Intramyocardial delivery of BM-MNC after surgical repair in Ebstein anomaly can be performed safely. Echocardiography variables suggest a positive impact of cell delivery on the RV myocardium with improvements in both RV size and wall motion over time. Additional follow-up and comparison to control groups are required to better characterize the impact of cell therapy on the myopathic RV in Ebstein anomaly.